Mechanisms of calcineurin inhibitor-induced neurotoxicity

The calcineurin inhibitors cyclosporin A (CyA) and FK506 are widely used as immunosuppressants in human organ transplantation. The main mechanism for their action is the suppression in T cells of calcineurin activity, a Ca²⁺ and calmodulin-dependent protein phosphatase. A range of side effects are observed in patients on CyA and FK506, and prominent among them is neurotoxicity. In nerve cells, calcineurin is a critical regulator of a diverse array of proteins, leading to both short- and long-term effects on neuronal excitability and function. Some of these roles include the regulation of synaptic transmission, ion channels, and gene transcription, all of which are important in basic brain function, as well as higher-order processes such as learning and memory. In addition, exposure of the central nervous system to CyA and FK506 is hindered by a physical barrier, the blood-brain barrier. This review outlines possible mechanisms for calcineurin-mediated neurotoxicity. This includes the protective role of the blood-brain barrier and the role of calcineurin in the regulation of neuronal function. It follows that a combination of the inhibition of calcineurin function within neurons and the nature of the exposure of neuronal tissue to calcineurin inhibitors may account for the diverse array of neurotoxic symptoms.